The present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for inhibiting a retroviral infection and in particular an HIV infection, processes for making the compounds and synthetic intermediates employed in the processes.
Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants. Some of the more important retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by the retrovirus.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag, gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. 58 899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS involve administration of compounds such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (DDC), 2xe2x80x2,3xe2x80x2-dideoxyinosine (DDI), d4T and 3TC and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Recently the HIV protease inhibitors ritonavir, saquinavir and indinavir have been approved in the U.S. for treatment of HIV infections. However, there is a continuing need for improved HIV protease inhibitors.
In accordance with the present invention, there is a compound of the formula I: 
wherein R1 and R2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;
R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl;
R4 is aryl or heterocyclic;
R5 is 
wherein n is 1, 2 or 3, m is 1, 2 or 3, mxe2x80x2 is 1 or 2, X is O, S or NH, Y is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R6)xe2x80x94 wherein R6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x3 is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R6xe2x80x3)xe2x80x94 wherein R6xe2x80x3 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x2 is xe2x80x94N(R6xe2x80x2)xe2x80x94 wherein R6xe2x80x2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH; and
L1 is
a) xe2x80x94Oxe2x80x94,
b) xe2x80x94Sxe2x80x94,
c) xe2x80x94N(R7)xe2x80x94 wherein R7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl,
d) xe2x80x94O-alkylenyl-,
e) xe2x80x94S-alkylenyl-,
f) xe2x80x94S(O)-alkylenyl-,
g) xe2x80x94S(O)2-alkylenyl-,
h) xe2x80x94N(R7)-alkylenyl- wherein R7 is defined as above,
i) -alkylenyl-Oxe2x80x94,
j) -alkylenyl-Sxe2x80x94,
k) alkylenyl-N(R7)xe2x80x94 wherein R7 is defined as above,
i) alkylenyl or
m) alkenylenyl;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Preferred compounds are compounds of the formula I wherein R1 and R2 are arylalkyl, R3 is loweralkyl, R4 is aryl, R5 is 
wherein X, Y, Yxe2x80x2, Yxe2x80x3, Z, R6xe2x80x3, n, m and mxe2x80x2 are defined as above and L1 is xe2x80x94O-alkylenyl.
More preferred compounds are compounds of the formula I wherein R1 and R2 are benzyl or R1 is benzyl and R2 is loweralkyl, R3 is loweralkyl, R4 is (a) phenyl which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo or (b) pyridyl or pyrimidinyl either of which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo, R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein m is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen and
L1 is xe2x80x94Oxe2x80x94CH2xe2x80x94.
Even more preferred compounds are compounds of the formula I wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl, R4 is
2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen and
L1 is xe2x80x94Oxe2x80x94CH2xe2x80x94.
Most preferred compounds are compounds of the formula I wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl, R4 is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen and
L1 is xe2x80x94Oxe2x80x94CH2xe2x80x94.
Most highly preferred compounds are compounds of the formula I wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl, R4 is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94 and
L1 is xe2x80x94Oxe2x80x94CH2xe2x80x94.
Examples of highly and most highly preferred compounds of the formula I are selected from the group consisting of: (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethyl butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-thionyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,4,6-trimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methylbutanoyl) amino-1,6-diphenylhexane; (2S,3S,5S)-2-(4-fluoro-2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl) amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-pyrrolidin-2-onyl)-3-methyl-butanoyl) amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-pyrrolidin-2,5-dionyl)-3-methyl-butanoyl) amino-1,6-diphenylhexane; (2S,3S,5S)-2-(trans-3-(2,6-dimethylphenyl) propenoyl) amino-3-hydroxy-5-(2S-1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl) amino-1,6-diphenylhexane; (2S,3S,5S)-2-(3-(2,6-dimethylphenyl) propanoyl) amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl) amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(4-aza-1-tetrahydro-pyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1-phenyl-6-methylheptane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl)amino-1-phenyl-6-methylheptane; and
(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(4-aza-4,5-dehydro-1-pyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
The most highly preferred compound of the formula I is (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
In some circumstances it is preferred to be able to prepare (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane (or a pharmaceutically acceptable salt, ester or prodrug thereof) as an amorphous solid. Such an amorphous solid can be prepared by dissolving (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in an organic solvent (for example, ethanol, isopropanol, acetone, acetonitrile and the like) and then adding the solution to water. Preferably, (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(l -tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane is dissolved in ethanol (from about 2 to about 4 ml g) and the ethanolic solution is added with stirring to water (from about 10 about 100 mL/g) to provide amorphous (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane.
Another embodiment of the present invention comprises an HIV protease inhibiting compound comprising a substituent of the formula II: 
wherein R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl; and
R5 is 
wherein n is 1,2 or 3, m is 1,2 or 3, m is 1 or 2, X is O, S or NH, Y is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R6)xe2x80x94 wherein R6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x3 is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R6xe2x80x3)xe2x80x94 wherein R6xe2x80x3 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x2 is xe2x80x94N(R6xe2x80x2)xe2x80x94 wherein R6xe2x80x2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH.
Preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula II wherein R3 is loweralkyl and R5 is 
wherein X, Y, Yxe2x80x2, Yxe2x80x3, Z, R6xe2x80x3, n, m and mxe2x80x2 are defined as above.
More preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula II wherein R3 is loweralkyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Even more preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula II wherein R3 is isopropyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Most preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula II wherein R3 is isopropyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Most highly preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula II wherein R3 is isopropyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94.
Examples of such HIV protease inhibiting compounds include;
cis-N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide;
cis-N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-thiophenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide; and
4-Amino-N-((2syn, 3S)-2-hydroxy-4-phenyl-3-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoylamino)-butyl)-N-isobutyl-benzenesulfonamide; and the like;
or pharmaceutically acceptable salts thereof.
Such HIV protease inhibiting compounds comprising a substituent of the formula it can be prepared by coupling a suitable intermediate or precursor having an amino group (xe2x80x94NH2 or xe2x80x94NHR* wherein R* is loweralkyl), a hydroxyl group (xe2x80x94OH) or a thiol group (xe2x80x94SH) to the compound of the formula III or a salt or an activated ester derivative thereof: 
wherein R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl; and R5 is 
wherein n is 1, 2 or 3, m is 1, 2 or 3, mxe2x80x2 is 1 or 2, X is O, S or NH, Y is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R6)xe2x80x94 wherein R6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x3 is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R6xe2x80x3)xe2x80x94 wherein R6xe2x80x3 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x2 is xe2x80x94N(R6xe2x80x2)xe2x80x94 wherein R6xe2x80x2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH.
Preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R3 is loweralkyl and R5 is 
wherein X, Y, Yxe2x80x2, Yxe2x80x3, Z, R6xe2x80x3, n, m and mxe2x80x2 are defined as above.
More preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R3 is loweralkyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2, is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Even more preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R3 is isopropyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Most preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R3 is isopropyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Most highly preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R3 is isopropyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention.
The terms xe2x80x9cSxe2x80x9d and xe2x80x9cRxe2x80x9d configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene and Wuts, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (John Wiley and Sons, New York (1991)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichioroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-di methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyt, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term xe2x80x9cactivated ester derivativexe2x80x9d as used herein refers to acid halides such as acid chlorides, and activated esters including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters, thiophenol derived esters, propylphosphonic acid derived anhydrides and the like.
The term xe2x80x9calkanoylxe2x80x9d as used herein refers to R19C(O)xe2x80x94 wherein R19 is a loweralkyl group.
The term xe2x80x9calkenylenylxe2x80x9d as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like.
The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9cthioalkoxyxe2x80x9d as used herein refer to R15Oxe2x80x94 and R15Sxe2x80x94, respectively, wherein R15 is a loweralkyl group.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to R22Oxe2x80x94R23Oxe2x80x94 wherein R22 is loweralkyl as defined above and R23 is an alkylenyl group. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkoxy group appended to a loweralkyl radical.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein refers to R20C(O)xe2x80x94 wherein R20 is an alkoxy group.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to xe2x80x94NHR16 wherein R16 is a loweralkyl group.
The term xe2x80x9calkylaminocarbonylxe2x80x9d as used herein refers to R21C(O)xe2x80x94 wherein R21 is an alkylamino group.
The term xe2x80x9calkylenylxe2x80x9d as used herein refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene (xe2x80x94CH2xe2x80x94), 1,2-ethylene (xe2x80x94CH2CH2xe2x80x94), 1,1-ethylene=CHxe2x80x94CH3, 1,3-propylene (xe2x80x94CH2CH2CH2xe2x80x94), 2,2-dimethylpropylene (xe2x80x94CH2C(CH3)2CH2xe2x80x94), and the like.
The term xe2x80x9caminocarbonylxe2x80x9d as used herein refers to xe2x80x94C(O)NH2.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system comprising 6 to 12 carbon atoms and having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxycarbonyl, thioalkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, mercapto, nitro, carboxaldehyde, carboxy and hydroxy.
The term xe2x80x9carylalkylxe2x80x9d as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to xe2x80x94NR16R17 wherein R16 and R17 are independently selected from loweralkyl groups.
The term xe2x80x9cdialkylaminocarbonylxe2x80x9d as used herein refers to R22C(O)xe2x80x94 wherein R22 is a dialkylamino group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to R18Oxe2x80x94 wherein R18 is a haloalkyl group.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to a loweralkyl group in which one or more hydrogen atoms are replaced by halogen, for example, chloromethyl, chloroethyl, trifluoromethyl and the like.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogen atoms; and includes a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; two sulfur atoms in non-adjacent positions; two sulfur atoms in adjacent positions and one nitrogen atom; two adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6-and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, bistetrahydorfuranyl or benzothienyl and the like). Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl. Heterocyclics also include compounds of the formula 
wherein X* is xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94, Y* is xe2x80x94C(O)xe2x80x94 or [xe2x80x94C(Rxe2x80x3)2xe2x80x94]v wherein Rxe2x80x3 is hydrogen or C1-C4-alkyl and v is 1, 2 or 3 and Z* is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94; such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.
Heterocyclics can be unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of hydroxy, halo, oxo (xe2x95x90O), alkylimino (R*Nxe2x95x90 wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, xe2x80x94COOH, xe2x80x94SO3H and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an hydroxy group.
The term xe2x80x9cloweralkylxe2x80x9d as used herein refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term xe2x80x9cthioalkoxyalkylxe2x80x9d as used herein refers to a thioalkoxy group appended to a loweralkyl radical.
The compound of the invention of formula I can be prepared as shown in Schemes I-IV. As outlined in Scheme I, intermediates 1 and 2 (wherein P1 is an N-protecting group, for example, t-butyloxycarbonyl) can be coupled using standard peptide coupling reagents and methods, for example, reaction of 1 and 2 in the presence of 1-hydroxybenzotriazole and a diimide such as dicyclohexylcarbodiimide (DCC) or N-ethyl-Nxe2x80x2-dimethylaminopropyl carbodiimide (EDAC) and the like to give 3. Alternatively, a salt or an activated ester derivative of intermediate 1 (for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride) can be reacted with intermediate 2.
Compound 3 can be N-deprotected to give compound 4. N-deprotection of 3 wherein P1 (especially wherein P1 is t-butyloxycarbonyl) is an acid labile N-protecting group can lead to formation of impurities resulting from migration of the acyl group R4xe2x80x94L1xe2x80x94C(O)xe2x80x94 from the amino group to the hydroxyl group. The formation of this impurity can be minimized or eliminated by performing the deprotection using (1) trifluoroacetic acid in methylene chloride or (2) concentrated hydrochloric acid (from about 2 molar equivalents to about 6 molar equivalents, preferably, from about 2 molar equivalents to about 4 molar equivalents) in acetic acid at about room temperature. A preferred N-deprotection method comprises reacting compound 3 (wherein P1 is t-butyloxycarbonyl) with concentrated hydrochloric acid (from about 10 to about 20 molar equivalents) in acetonitrile (from about 2 to about 10 liters/kilogram of compound 3) at a temperature of from about 0xc2x0 C. to about 5xc2x0 C. Compound 5 or an activated ester derivative thereof can then be coupled to compound 4 to give the compound of the formula I (i.e., 6.
An alternative process is shown in Scheme IIA. Compound 7 (wherein P2 is an N-protecting group, for example, benzyloxycarbonyl) can be coupled to compound a, or a salt or an activated ester derivative thereof (for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride), to give 8. Compound a can be N-deprotected to give 9 Compound 2 can be coupled with compound 1, or an activated ester derivative thereof, to give the compound of the formula I (i.e., 6).
Scheme IIB shows a preferred alternative process wherein the N-protected amino alcohol 7a (P3 is hydrogen and P4 is an N-protecting group or both P3 and P4 are N-protecting groups, preferably, P3 and P4 are benzyl) is reacted with from about 1 to about 1.3 molar equivalents of carboxylic acid 5 or a salt or an activated ester derivative thereof (for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride in ethyl acetate or THF or oxalyl chloride in toluene/DMF and the like) in the presence of from about 1.0 to about 4.0 molar equivalents (preferably, from about 2.5 to about 3.5 molar equivalents) of an organic amine base (for example, imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole, 4-nitroimidazole, pyridine, N,N-dimethylaminopyridine, 1,2,4-triazole, pyrrole, 3-methylpyrrole, triethylamine or N-methylmorpholine and the like) or from about 1 to about 20 molar equivalents of an inorganic base (for example, sodium carbonate or sodium bicarbonate and the like) in an inert solvent (for example, ethyl acetate, dimethylformamide, THF, acetonitrile, isopropyl acetate or toluene and the like) at a temperature of from about 0xc2x0 C. to about 50xc2x0 C. to provide compound S. Preferred organic amine bases include imidazole and 1,2,4-triazole.
N-Debenzylation of 8a (for example, using hydrogen and a hydrogenation catalyst or Pd/C and a formic acid salt (for example, ammonium formate and the like) or Pd/C and formic acid and the like) provides 9. Compound 9 can be advantageously purified by crystallization with an organic carboxylic acid (for example, S-pyroglutamic acid, succinic acid or fumaric acid and the like). A preferred organic carboxylic acid is S-pyroglutamic acid.
Compound 9 (or an organic carboxylic acid salt of compound 9) is reacted with from about 1.0 to about 1.3 molar equivalents of carboxylic acid 1 or a salt or an activated ester derivative thereof (for example, the acid chloride) in the presence of (1) from about 4 to about 8 molar equivalents (preferably, from about 5 to about 7 molar equivalents) of an inorganic base (for example, NaHCO3, Na2CO3, KHCO3, K2CO3, NaOH or KOH and the like) in an inert solvent (for example, 1:1 ethyl acetate/water or isopropyl acetate/water or toluene/water or THF/water and the like) at about room temperature or (2) from about 1.0 to about 4.0 molar equivalents (preferably, from about 2.5 to about 3.5 molar equivalents) of an organic amine base (for example, imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole, 4-nitroimidazole, pyridine, N,N-dimethylaminopyridine, 1,2,4-triazole, pyrrole, 3-methylpyrrole, triethylamine or N-methylmorpholine and the like) in an inert solvent (for example, ethyl acetate, isopropyl acetate, THF, toluene, acetonitrile, dimethylformamide and the like) at a temperature of from about 0xc2x0 C. to about 50xc2x0 C. to provide compound 6.
In a preferred embodiment of the invention (shown in Scheme III), intermediate compound 5 has the formula of compound 10 (R3 is as defined for the compound of formula I and is preferably isopropyl). Compound 10 can be prepared in variety ways as shown in Scheme III. In one method, amino acid 11 (either as the free carboxylic acid or as the carboxylic acid ester (i.e., loweralkyl ester)) is converted to carbamate 12 (Rxe2x80x3 is phenyl, loweralkyl-substituted phenyl, halo-substituted phenyl, nitro-substituted phenyl, trifluoromethylphenyl and the like) by reaction with the appropriate chloroformate ester and the like. Reaction of carbamate 12 with from about 1.0 to about 1.5 molar equivalents of amine 13 or an acid addition salt thereof (Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, methyl t-butyl ether, dimethoxyethane, THF/water, dimethoxyethane/water, toluene or heptane and the like) in the presence of a base (for example, LiOH, NaOH, Li2CO3, Na2CO3, lithium phenoxide or sodium phenoxide and the like) in the amount of from about 2.5 to about 3.5 molar equivalents provides urea 14. Urea 14 can be isolated and reacted further or can be converted in situ to cyclic urea 10 by reaction in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) with a base (for example, potassium t-butoxide, sodium hydride, potassium hydride or dimethylaminopyridine and the like) in the amount of from about 2.0 to about 5.0 molar equivalents. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 10.
Alternatively, amino acid 11 (either as the free carboxylic acid or as the carboxylic acid ester) is converted to urea 14 by reaction with from about 1.0 to about 1.5 molar equivalents of isocyanate 15 (Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the presence of a base.
In yet another alternative, amino acid 11 (either as the free carboxylic acid or as the carboxylic acid ester) is converted to diamine 16 by reaction with from about 1.0 to about 1.5 molar equivalents of amine 13 or an N-protected derivative thereof (Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the presence of a base (for example, NaH or potassium t-butoxide and the like) in the amount of from about 1.0 to about 4.0 molar equivalents. N-deprotection is required if the N-protected derivative of 13 was used. Reaction of diamine 16 with a carbonyl equivalent 17 (for example, phosgene, carbonyidiimidazole and the like wherein Qxe2x80x2 and Qxe2x80x3 are leaving groups such as Cl, Br, I, xe2x80x94O-loweralkyl, xe2x80x94O-aryl or imidazolyl and the like) in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the presence of a base (for example, NaH or potassium t-butoxide and the like and the like) in the amount of from about 2.0 to about 4.0 molar equivalents provides cyclic urea 10. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 10.
In yet another alternative shown in Scheme IV, compound 11 (either as the free carboxylic acid or as the carboxylic acid ester (i.e., loweralkyl ester)) is reacted with acrylonitrile according to J. Am. Chem. Soc. 72, 2599 (1950) to give aminonitrile 18. Alternatively, acrylonitrile can be replaced with 3-chloropropionitrile to provide 18. N-protection of aminonitrile 18 as the carbamate (R30 is loweralkyl or phenyl or haloalkyl (for example, 2-chloroethyl, 2-bromoethyl and the like) and the like) using standard conditions (for example, reaction of the amine with the appropriate chloroformate ester (CIC(O)OR30 wherein R30 is loweralkyl, phenyl, haloalkyl and the like) neat or in an inert solvent (for example, water, THF and the like) in the presence of an inorganic base (for example, NaOH, KOH, K2CO3 and the like) or an organic base (for example, an alkylamine or dialkylamine and the like) and the like) provides compound 19. Hydrogenation of 19 in the presence of a catalyst (for example, Nixe2x80x94Al alloy (basic) or Raney nickel (neutral or basic) or PtO2 (acidic) and the like) in an inert solvent (for example, water or methanol or ethanol or THF and the like) provides cyclic urea 10. In a preferred process, compound 19 is hydrogenated in the presence of a Nixe2x80x94Al alloy catalyst in an inert solvent (for example, water or methanol or ethanol or THF and the like) in the presence of a base (for example, KOH or NaOH or LiOH or an organic amine base and the like) in the amount of from about 1.1 to about 5 molar equivalents to provide cyclic urea 10. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 10.
Alternatively, hydrogenation of compound 18 (as described above for compound 19) provides diamine 16 which can be converted to compound 10 as previously described. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 10. 
Key intermediates for the preparation of the compounds of the invention include compounds of the formula III as described above and compounds of the formula IV: 
or a salt thereof,
wherein P3 and P4 are independently selected from hydrogen or an N-protecting group;
R1 and R2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;
R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl; and
R5is 
wherein n is 1, 2 or 3, m is 1, 2 or 3, mxe2x80x2 is 1 or 2, X is O, S or NH, Y is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R6)xe2x80x94 wherein R6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x3 is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R6xe2x80x3)xe2x80x94 wherein R6xe2x80x3 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Yxe2x80x2 is xe2x80x94N(R6xe2x80x2)xe2x80x94 wherein R6xe2x80x2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH.
Preferred compounds are compounds of the formula IV wherein P3 and P4 are hydrogen or benzyl, R1 and R2 are arylalkyl, R3 is loweralkyl and R5 is 
wherein X, Y, Yxe2x80x2, Yxe2x80x3, Z, R6xe2x80x3, m and mxe2x80x2 are defined as above.
More preferred compounds are compounds of the formula IV wherein R1 and R2 are benzyl or R, is benzyl and R2 is loweralkyl, R3 is loweralkyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Even more preferred compounds are compounds of the formula IV wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein m is 1 or 2, X is O, Y is xe2x80x94CH2xe2x80x94 and Z is O, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Most preferred compounds are compounds of the formula IV wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Z is O and Y is xe2x80x94NHxe2x80x94, 
wherein mxe2x80x2 is 1, X is O, Yxe2x80x3 is xe2x80x94NHxe2x80x94 and Yxe2x80x2 is xe2x80x94NHxe2x80x94 or 
wherein X is O and R6xe2x80x3 is hydrogen.
Most highly preferred compounds are compounds of the formula IV wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl and R5 is 
wherein n is 1 or 2, X is O or S and Y is xe2x80x94CH2 or xe2x80x94NHxe2x80x94.
Preferred salts of the compound of formula IV are organic carboxylic acid salts, especially the (S)-pyroglutamic acid salt.
The following examples will serve to further illustrate the preparation of the novel compounds of the invention.